Heteroarylcarbamoylbenzene derivative

Abstract

Compounds represented by formula (I): as well as their pharmaceutically acceptable salts are disclosed. The compounds are useful as glucokinase activating agents for the treatment of diabetes and related conditions. Compositions and methods of treatment are also included.

What is claimed is: 
     
       1. A compound represented by formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 X 1  represents oxygen, sulfur or NH; 
 X 2  represents oxygen, sulfur or CH 2 ; 
 R 1  represents 1 or 2 substituents optionally present on Ring A which are selected from the group consisting of: alkylsulfonyl, alkanoyl, lower alkyl, hydroxyalkyl, hydroxy, alkylcarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkylthio, alkoxy, dialkylcarbamoyl, alkoxycarbonylamino, alkoxycarbonyl, halogen atoms, alkanoylaminoalkyl, alkoxycarbonylaminoalkyl, alkylsulfonylaminoalkyl, cyano and trifluoromethyl; 
 R 2  represents: a C3-7 cyclic alkyl group wherein one of the constituent carbon atoms of the ring, except for the carbon atom, which is bonded to X 2 , is optionally replaced with oxygen, NH, N-alkanoyl or CONH;
 a straight-chain or branched lower alkyl group or a lower alkenyl group, optionally having a substituent selected from the group consisting of halogen atoms, carboxyl, alkoxycarbonyl, hydroxy, amino optionally substituted with 1 or 2 alkanoyl or lower alkyl groups, alkoxy and N-alkylcarbamoyl; 
 
 R 3  represents 1 or 2 substituents optionally present on Ring B which are selected from the group consisting of: lower alkyl; alkoxy; alkylamino; lower dialkylamino; halo; trifluoromethyl; hydroxyalkyl, wherein the hydrogen of the hydroxy in the hydroxyalkyl group may be substituted with lower alkyl; aminoalkyl; alkanoyl; carboxyl; alkoxycarbonyl and cyano; 
 the following formula (II): 
 
       
         
           
           
               
               
           
         
       
       represents a pyridyl ring;
 and formula (III): 
 
       
         
           
           
               
               
           
         
       
       represents a pyridyl ring. 
     
     
       2. A compound according to  claim 1  wherein X 1  is O or S, and X 2  is O or CH 2 . 
     
     
       3. A compound according to  claim 1  wherein R 1  is alkylsulfonyl, alkanoyl, hydroxyalkyl, alkylcarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, dialkylcarbamoyl, alkoxycarbonylamino, halogen atoms, alkanoylaminoalkyl, alkylsulfonylaminoalkyl or alkoxycarbonylaminoalkyl. 
     
     
       4. A compound according to  claim 1  wherein R 1  is alkylsulfonyl, alkanoyl, hydroxyalkyl, alkylcarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, dialkylcarbamoyl, alkoxycarbonylamino, halogen atoms, alkanoylaminoalkyl, alkylsulfonylaminoalkyl or alkoxycarbonylaminoalkyl. 
     
     
       5. A compound according to  claim 1  wherein R 1  is alkylsulfonyl, alkanoyl, hydroxyalkyl, alkanoylaminoalkyl, alkylsulfonylaminoalkyl or alkoxycarbonylaminoalkyl. 
     
     
       6. A compound according to  claim 5  wherein R 1  is alkylsulfonyl, alkanoyl or hydroxyalkyl. 
     
     
       7. A compound according to  claim 1  wherein R 2  is
 a C3-7 cyclic alkyl group in which one of the carbon atoms of the ring is optionally replaced with oxygen, NH or N-alkanoyl, or 
 a straight-chain or branched lower alkyl group or a lower alkenyl group, optionally substituted with a halo, carboxyl, alkoxycarbonyl, hydroxy, amino optionally substituted with 1 or 2 lower alkyl groups, alkoxy, N-alkylcarbamoyl or alkanoylamino. 
 
     
     
       8. A compound according to  claim 1  wherein R 3  is lower alkyl; alkoxy; halo; hydroxyalkyl in which the hydrogen of the hydroxy in the hydroxyalkyl group may be substituted with lower alkyl; aminoalkyl or alkanoyl. 
     
     
       9. A compound according to  claim 1  wherein R 3  is lower alkyl or hydroxyalkyl in which the hydrogen of the hydroxy in the hydroxyalkyl group may be substituted with lower alkyl. 
     
     
       10. A pharmaceutical composition comprised of a compound in accordance with  claim 1  in combination with a pharmaceutically acceptable carrier. 
     
     
       11. A pharmaceutical composition in accordance with  claim 10  further comprising a compound selected from the group consisting of:
 (a) other glucokinase activators 
 (b) bisguanides 
 (c) PPAR agonists 
 (d) insulin 
 (e) somatostatin 
 (f) α-glucosidase inhibitors, and 
 (g) insulin secretagogues. 
 
     
     
       12. A method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with  claim 1  in an amount that is effective to treat diabetes. 
     
     
       13. A method of treating obesity in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with  claim 1  in an amount that is effective to treat diabetes. 
     
     
       14. A compound in accordance with  claim 1 , selected from the group consisting of:
 3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-1-methyl-1H-pyrazol-3-yl)benzamide, 3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazol-3-yl)benzamide, 3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 5-(6-ethanesulfonylpyridin-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)-benzamide, 3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydrofuran-3-yl)benzamide, N-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide, 5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyrazol-3-yl)benzamide, 3-(6-methanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(pyrazol-3-yl)benzamide, 3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-1-methyl-1H-pyrazol-3-yl)benzamide, 3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide, 5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-1-methyl-1H-pyrazol-3-yl)benzamide, 5-(2-chloro-1-methyl-ethoxy)-3-(6-ethanesulfonylpyridin-3-yloxy)-N-1-methyl-1H-pyrazol-3-yl)benzamide, 5-(2-hydroxy-1-methyl-ethoxy)-3-(6-isopropylsulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 5-(2-hydroxy-1-methyl-ethoxy)-N-1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide, 5-(2-fluoro-1-fluoromethyl-ethoxy)-N-1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide, 5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide, 5-(2-fluoro-1-fluoromethyl-ethoxy)-N-1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide, 2-[3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionic acid, 
 
       and the pharmaceutically acceptable salts thereof. 
     
     
       15. A compound in accordance with  claim 1  selected from the group consisting of: 3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonyl-pyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide, 5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonyl-pyridin-3-yloxy)-N-(pyrazol-3-yl)benzamide and the pharmaceutically acceptable salts thereof. 
     
     
       16. A compound represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
       17. A compound in accordance with  claim 16  of the formula: 
       
         
           
           
               
               
           
         
       
     
     
       18. A pharmaceutical composition comprising a compound in accordance with  claim 16  in combination with a pharmaceutically acceptable carrier. 
     
     
       19. A pharmaceutical composition comprising a compound in accordance with  claim 17  in combination with a pharmaceutically acceptable carrier. 
     
     
       20. A pharmaceutical composition comprising a compound in accordance with  claim 14  in combination with a pharmaceutically acceptable carrier. 
     
     
       21. A pharmaceutical composition comprising a compound in accordance with  claim 15  in combination with a pharmaceutically acceptable carrier. 
     
     
       22. A method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with  claim 14  in an amount effective to treat type 2 diabetes. 
     
     
       23. A method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with  claim 16  in an amount effective to treat type 2 diabetes.